Crystal structure of a voltage-gated sodium channel in two potentially inactivated states.
Crystal structure of a voltage-gated sodium channel in two potentially inactivated states.
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DOI：
10.1038/nature11077
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发表时间：
2012-05-20
期刊：
影响因子：
64.8
通讯作者：
Catterall, William A.
中科院分区：
文献类型：
--
作者：
Payandeh, Jian;El-Din, Tamer M. Gamal;Scheuer, Todd;Zheng, Ning;Catterall, William A.
在可兴奋细胞中，电压门控钠（NaV）通道激活以启动动作电位，然后经历快速和缓慢的失活过程，终止其离子电导。失活是NaV通道功能的标志，对于控制膜兴奋性至关重要，但这一过程的结构基础仍然难以捉摸。在这里，我们报告的结晶快照的野生型NavAb通道Arcobacter butzleri捕获在两个潜在的灭活状态在3.2 μ m分辨率。与NavAb S6-半胱氨酸突变体的先前结构相比，孔衬S6螺旋和细胞内活化门经历了显著的重排，其中一对S6片段朝向中心孔轴塌陷，另一对S6片段向外移动以产生显著的二聚体的二聚体构型。在我们的野生型NavAb模型中观察到全局结构不对称性增加，重塑了孔的细胞外末端的离子选择性过滤器，中心腔及其类似于哺乳动物药物受体位点的残基，以及侧孔开窗。电压敏感结构域也围绕NavAb中的孔模块的周边移动，并且局部结构变化鉴定了连接参与NaV通道门控和失活的远端分子决定簇的保守相互作用网络。这些潜在的失活状态结构为NaV通道门控提供了新的见解，并为一系列衰弱性NaV通道病的药物开发和治疗提供了新的途径。
In excitable cells, voltage-gated sodium (NaV) channels activate to initiate action potentials and then undergo fast and slow inactivation processes that terminate their ionic conductance. Inactivation is a hallmark of NaV channel function and is critical for control of membrane excitability, but the structural basis for this process has remained elusive. Here we report crystallographic snapshots of the wild-type NavAb channel from Arcobacter butzleri captured in two potentially inactivated states at 3.2 Å resolution. Compared to previous structures of NavAb S6-cysteine mutants, the pore-lining S6 helices and the intracellular activation gate have undergone significant rearrangements in which one pair of S6 segments has collapsed toward the central pore axis and the other S6 pair has moved outward to produce a striking dimer-of-dimers configuration. An increase in global structural asymmetry is observed throughout our wild-type NavAb models, reshaping the ion selectivity filter at the extracellular end of the pore, the central cavity and its residues analogous to the mammalian drug receptor site, and the lateral pore fenestrations. The voltage-sensing domains also shift around the perimeter of the pore module in NavAb, and local structural changes identify a conserved interaction network that connects distant molecular determinants involved in NaV channel gating and inactivation. These potential inactivated-state structures provide new insights into NaV channel gating and novel avenues to drug development and therapy for a range of debilitating NaV channelopathies.
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影响因子：
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